The present invention relates to novel, reproducible methods for the preparation of crystalline forms of sertraline hydrochloride Forms III and V through X, as well as the preparation of an amorphous form of sertraline hydrochloride.
Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula 
is approved, under the trademark Zoloft(copyright), by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. Pat. No. 4,536,518 (xe2x80x9cthe ""518 patentxe2x80x9d) describes the preparation of sertraline hydrochloride with a melting point of 243-245xc2x0 C., by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the sertraline hydrochloride so produced are not otherwise disclosed.
According to U.S. Pat. No. 5,248,699 (xe2x80x9cthe ""699 patentxe2x80x9d), the sertraline hydrochloride produced by the method of the ""518 patent has a crystalline form denominated xe2x80x9cForm II.xe2x80x9d The ""699 patent discloses four other polymorphs I, III, IV, and V, and characterizes them by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. The ""699 patent reports that Form II is produced by rapid crystallization of sertraline hydrochloride from an organic solvent, including isopropyl alcohol, ethyl acetate or hexane, and generally describes methods for making sertraline hydrochloride Forms I-V. According to this patent, the preferential formation of Forms I, II or IV in an acidic solution consisting of isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on the rapidity of crystallization. Form I is described as being made by crystallizing sertraline hydrochloride in an acidic solution using an organic solvent such as those listed above. The crystallization of Form I is carried out at a temperature from about 20xc2x0 C. to about the solvent reflux temperature, preferably from about 40xc2x0 to 60xc2x0 C. The only method described in this patent for making Forms II and IV is by the rapid crystallization of sertraline hydrochloride from an organic solvent such as those listed above. Slow crystallization or granulation of sertraline hydrochloride is said to produce Form I. Form III is described as being formed by heating Forms I, II or IV to temperatures above about 180xc2x0 C. Granulating either of Forms II, III or IV in any of the solvents listed above at a temperature from about 40xc2x0 C. to 60xc2x0 C. is said to cause conversion to Form I. The only method described in this patent for making Form V is by sublimation of sertraline hydrochloride Form I at reduced pressure and at a temperature from about 180-190xc2x0 C. However, in our hands attempts to repeat this procedure to obtain Form V have been unsuccessful.
The present invention relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline hydrochloride in a suitable solvent; removing the solvent; and drying to form sertraline hydrochloride Form V.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline base in a solvent; adding hydrogen chloride to the solvent to reduce the pH of the solution or suspension; and isolating sertraline hydrochloride Form V from the solution or suspension.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the step of drying sertraline hydrochloride Form VII.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline hydrochloride in water; adding a sufficient amount of hydrochloric acid or hydrogen chloride to facilitate precipitation of sertraline hydrochloride; removing the water; and isolating sertraline hydrochloride Form V.
The present invention also relates to a process for making sertraline hydrochloride Form VI comprising the steps of: dissolving sertraline base in a solvent; adding hydrochloric acid to the solvent; and isolating sertraline hydrochloride Form VI without further drying.
The present invention also relates to a process for making sertraline hydrochloride Form VI comprising the steps of: dissolving or suspending sertraline hydrochloride in ethanol or methanol; stirring for a time sufficient to induce the transformation of sertraline hydrochloride to sertraline hydrochloride Form VI; and isolating sertraline hydrochloride Form VI.
The present invention also relates to a process for making sertraline hydrochloride Form VIII comprising the steps of: suspending sertraline base in water; adding hydrogen chloride to the water; and filtrating the precipitate so obtained without further drying.
The present invention also relates to a process for making sertraline hydrochloride Form VIII comprising the steps of: suspending or dissolving sertraline hydrochloride ethanolate Form VI or sertraline hydrochloride Form II in water or a mixture of water and isopropyl alcohol; and isolating sertraline hydrochloride Form VIII.
The present invention also relates to a process for making sertraline hydrochloride Form III comprising the steps of: heating sertraline hydrochloride Form V or Form VI to a temperature sufficient, and for a time sufficient, to induce the transformation of sertraline hydrochloride Form V or Form VI to sertraline hydrochloride Form III; and isolating sertraline hydrochloride Form III.
The present invention also relates to a process for making amorphous sertraline hydrochloride comprising the steps of: suspending or dissolving sertraline base in a non-polar organic solvent; adding gaseous hydrochloric acid; and isolating amorphous sertraline hydrochloride.